TIME Study: Therapeutic Hypothermia for Infants With Mild Encephalopathy

Stanford University68 enrolled

Overview

The TIME study is a randomized, controlled trial to evaluate impact on early measures of neurodevelopment and the safety profile of therapeutic hypothermia in term neonates with Mild Hypoxic-Ischemic Encephalopathy who are \< 6 hours of age. Neurodevelopmental outcome will be assessed at 12-14 months of age. The study will enroll 68 neonates randomized to therapeutic hypothermia or normothermia across 5 centers in California.

The TIME study is a multi-center randomized, controlled trial of Therapeutic Hypothermia (TH) (33.5°C ± 0.5° for 72 hours) versus normothermia using targeted temperature management, initiated within 6 hours after birth in term neonates with Mild Hypoxic-Ischemic Encephalopathy (HIE). Mild encephalopathy will be identified using the 6 component modified Sarnat exam as in the Neonatal Research Network of the National Institute of Child Health and Human Development trials of TH for moderate-severe encephalopathy and will be expanded to include features of mild encephalopathy. Eligible subjects must demonstrate ≥ 2 exam abnormalities (mild, moderate, severe) but without evidence of moderate-severe encephalopathy (≥ 3 moderate or severe features). The primary outcome is neurodevelopmental outcome at 12-14 months of age. Secondary outcomes include evaluating the safety profile of therapeutic hypothermia in patients with Mild HIE. Therapeutic hypothermia is well tolerated and did not demonstrate serious safety concerns when evaluated in multiple large studies of neonates with moderate-severe HIE. It is now being applied by some practitioners to neonates with Mild HIE without systematic evidence of benefit or potential harm. This data will be necessary in order to develop and larger trial of efficacy to be determined at 2 years of age.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Hypoxic-Ischemic Encephalopathy Mild Neonatal Encephalopathy

Interventions

Therapeutic HypothermiaOTHER

Therapeutic hypothermia involves use of a servo-controlled device and blanket to lower the core body temperature by 3°C for 72 hours followed by a period of re-warming in which the temperature is increased by 0.5°C per hour for 6 hours until normothermia is achieved.

NormothermiaOTHER

Normothermia will be achieved using the same servo-controlled device and blanket to assure normothermia of the control arm. The goal temperature for normothermia is 36.5-37.3°C for 72 hours.

Eligibility

Sex: ALLMax age: 6 Hours

Medical Language ↔ Plain English

Inclusion Criteria (must meet all 3): 1. Neonates born at ≥ 36 0/7 weeks 2. Neonatal signs or contributing factors consistent with an acute peri-partum or intra-partum event (must meet a or b): 1. pH ≤ 7.0 or Base deficit ≥ 16 in any umbilical cord or baby specimen at ≤ 1 hr of age OR 2. No umbilical cord or baby blood gas at ≤ 1 hr of age OR pH 7.01-7.15 or Base deficit 10-15.9 in any cord or baby specimen at ≤ 1 hr of age AND at least one of the following * Apgar score at 10 min ≤ 5 * Continued need for resuscitation at 10 min (chest compressions, bag mask ventilation, intubation with positive pressure ventilation) * Acute Perinatal Event: uterine rupture, placental abruption, cord accident (prolapse, rupture, knot or tight nuchal cord), maternal trauma, maternal hemorrhage or cardiorespiratory arrest, fetal exsanguination from either vasa previa or feto-maternal hemorrhage * Fetal heart rate monitor pattern consistent with acute peripartum or intrapartum event (category III trace: no heart rate variability, presence of recurrent late or variable decelerations, bradycardia, or sinusoidal pattern) 3. Evidence of Mild Encephalopathy on Modified Sarnat Exam. * Presence of at least 2 signs of mild, moderate or severe encephalopathy with no more than 2 moderate or severe findings in the 6 tested categories (level of consciousness, spontaneous activity, posture, tone, neonatal reflexes (suck and moro), and autonomic nervous system Exclusion Criteria: * Patients \< 36 0/7 weeks birthweight \< 1800gm; congenital or chromosomal anomaly associated with abnormal neurodevelopment or death; patients with moderate or severe HIE (by Sarnat exam or presence of clinical or electrographic seizures) identified within 6 hours after birth; core body temperature \< 34°C for more than 1 hour prior to randomization.

Locations (5)

Loma Linda Children's Hospital

Loma Linda, California, United States

Benioff Children's Hospital Oakland

Oakland, California, United States

Children's Hospital Orange County

Orange, California, United States

Stanford University

Palo Alto, California, United States

Outcomes

Primary Outcomes

Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS)

Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) will be assessed at 12-14 months of age. The mean score for a 12 month old normally developing infant is 109 with a standard deviation of 16.5. Higher scores are associated with normal development.

Time frame: Assessment takes up to 15 minutes and will be conducted at 12-14 months of age

Alberta Infant Motors Scale (AIMS)

Alberta Infant Motors Scale (AIMS) will be assessed at 12-14 months of age. The AIMS score is determined by assessment of 4 positions and scoring the least and most mature position identified. The score is converted to a percentile for age with those in the 5th to 25th percentile identified as suspicious motor development and those with a score corresponding to \< 5th percentile being identified as abnormal motor development.

Time frame: Assessment takes up to 15 minutes and will be conducted at 12-14 months of age

Secondary Outcomes

Percentage of participants with sinus bradycardia

Investigators will determine the proportion of treated and control subjects who develop sinus bradycardia (HR \< 80) during the intervention period (72 hours).

Time frame: 72 hours

Percentage of participants thrombocytopenia

Investigators will determine the proportion of treated and control subjects who develop thrombocytopenia (platelet count of \< 150 x 109/L) during the intervention period

Time frame: 72 hours

Percentage of patients who require intubation and mechanical ventilation

Investigators will determine the proportion of treated and control subjects who require intubation and mechanical ventilation

Time frame: 72 hours

Central Contacts

Sonia L Bonifacio, MD

CONTACT

650-723-5711 soniab1@stanford.edu

Krisa Van Meurs, MD

CONTACT

650-723-5711 vanmeurs@stanford.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.